Drug abuse, including cigarette smoking, is inextricably linked to the physical environment. The behavioral and neural bases of drug-environment interactions have been widely studied in animal models of addiction but despite this and the recognized clinical importance of environmental context on treatment outcomes, very little empirical work has investigated drug environment reactivity in humans. The overarching goal of the current proposal is to address this gap through human laboratory, neuroimaging and clinical research. We previously developed and validated a method by which smokers identify and then photograph environments reliably associated (or not associated) with their smoking. In a series of studies we have demonstrated that personal smoking environment cues (PSEs) robustly elicit craving and promote smoking, and uniquely activate brain regions implicated in context-induced drug seeking, nicotine dependence and cessation including the hippocampus (HPC) and right anterior insula (aINS); and that activation in aINS is positively correlated with smoking behavior in response to viewing PSEs. In the proposed application, we will seek to further understand the neural and behavioral correlates of reactivity to PSEs and their role in smoking cessation treatment and outcomes. In Aim 1 we will evaluate the effects of varenicline versus nicotine replacement versus placebo on PSE reactivity in a sample of 120 smokers. In Aim 2, we will evaluate the effects 24-h abstinence on brain activation and functional coupling in response to PSE, standard smoking environments and proximal cues (e.g. picture of a lit cigarette) in a sample of 48 smokers. Smokers who have participated in laboratory (Aim 1 Study) and fMRI (Aim 2 Study) assessments will undergo a 10 week smoking cessation period. In Aim 3, we will evaluate associations between PSE reactivity and smoking cessation outcomes including time to lapse (i.e. first cigarette after quitting) and relapse (i.e. return to regular smoking). The proposed research will have significant scientific impact by fillin the critical gap between the recognized clinical importance of the environment in addictive behavior and the large preclinical database on drug-environment interactions. Clinical research and practice will also be impacted by determining the degree to which first-line medictions address environment reactivity, the development of a human analog of preclinical models of environment effects and the further refinement of a novel biomarker-PSE reactivity-that can be used to subtype patients and tailor intervention.